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The Journal of Membrane Biology

, Volume 252, Issue 4–5, pp 385–396 | Cite as

Untangling Direct and Domain-Mediated Interactions Between Nicotinic Acetylcholine Receptors in DHA-Rich Membranes

  • Kristen Woods
  • Liam Sharp
  • Grace BranniganEmail author
Article
  • 123 Downloads
Part of the following topical collections:
  1. Membrane and Receptor Dynamics

Abstract

At the neuromuscular junction (NMJ), the nicotinic acetylcholine receptor (nAChR) self-associates to give rise to rapid muscle movement. While lipid domains have maintained nAChR aggregates in vitro, their specific roles in nAChR clustering are currently unknown. In the present study, we carried out coarse-grained molecular dynamics simulations (CG-MD) of 1–4 nAChR molecules in two membrane environments: one mixture containing domain-forming, homoacidic lipids, and a second mixture consisting of heteroacidic lipids. Spontaneous dimerization of nAChRs was up to ten times more likely in domain-forming membranes; however, the effect was not significant in four-protein systems, suggesting that lipid domains are less critical to nAChR oligomerization when protein concentration is higher. With regard to lipid preferences, nAChRs consistently partitioned into liquid-disordered domains occupied by the omega-3 (\(\omega\)-3) fatty acid, docosahexaenoic acid (DHA); enrichment of DHA boundary lipids increased with protein concentration, particularly in homoacidic membranes. This result suggests dimer formation blocks access of saturated chains and cholesterol, but not polyunsaturated chains, to boundary lipid sites.

Keywords

Nicotinic acetylcholine receptor (nAChR) Polyunsaturated fatty acids (PUFAs) Domain formation Lipid–protein interactions Lipid rafts Docosahexaenoic acid (DHA) 

Notes

Acknowledgements

GB was supported by research Grants NSF MCB1330728 and NIH P01GM55876. GB and LM were also supported through a Grant from the Research Corporation for Scientific Advancement. This project was supported with computational resources from the National Science Foundation XSEDE program through allocation NSF-MCB110149, a local cluster funded by NSF-DBI1126052, the Rutgers University Office of Advanced Research Computing (OARC) and the Rutgers Discovery Informatics Institute (RDI2), which is supported by Rutgers and the State of New Jersey. We are grateful to Dr. Jérôme Hénin for his helpful suggestions throughout this study.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest. This research was supported in part by the National Science Foundation, the National Institutes of Health, and the Research Corporation for Scientific Advancement.

References

  1. Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89(1):73–120.  https://doi.org/10.1152/physrev.00015.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Althoff T, Hibbs RE, Banerjee S, Gouaux E (2014) X-ray structures of glucl in apo states reveal a gating mechanism of cys-loop receptors. Nature 512(7514):333–337.  https://doi.org/10.1038/nature13669 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Anholt R, Lindstrom J, Montal M (1980) Functional equivalence of monomeric and dimeric forms of purified acetylcholine receptors from torpedo californica in reconstituted lipid vesicles. Eur J Biochem 109:481–487CrossRefGoogle Scholar
  4. Antollini SS, Barrantes FJ (2016) Fatty acid regulation of voltage- and ligand-gated ion channel function. Front Physiol 7:573.  https://doi.org/10.3389/fphys.2016.00573 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Baaden M, Marrink SJ (2013) Coarse-grain modelling of protein–protein interactions. Curr Opin Struct Biol 23(6):878–886.  https://doi.org/10.1016/j.sbi.2013.09.004 CrossRefPubMedGoogle Scholar
  6. Baenziger JE, Corringer PJ (2011) 3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels. Neuropharmacology 60(1):116–125.  https://doi.org/10.1016/j.neuropharm.2010.08.007 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Baenziger JE, Hénault CM, Therien JPD, Sun J (2015) Nicotinic acetylcholine receptor-lipid interactions: mechanistic insight and biological function. Biochimica Biophysica Acta 1848(9):1806–1817.  https://doi.org/10.1016/j.bbamem.2015.03.010 CrossRefGoogle Scholar
  8. Baenziger JE, Domville JA, Therien JPD (2017) The role of cholesterol in the activation of nicotinic acetylcholine receptors. Curr Topics Memb 80:95–137.  https://doi.org/10.1016/bs.ctm.2017.05.002 CrossRefGoogle Scholar
  9. Barrantes FJ (2007) Cholesterol effects on nicotinic acetylcholine receptor. J Neurochem 103(s1):72–80CrossRefGoogle Scholar
  10. Barrantes FJ, Antollini SS, Blanton MP, Prieto M (2000) Topography of nicotinic acetylcholine receptor membrane-embedded domains. J Biol Chem 275(48):37333–37339CrossRefGoogle Scholar
  11. Barrantes FJ, Bermudez V, Borroni MV, Antollini SS, Pediconi MF, Baier JC, Bonini I, Gallegos C, Roccamo AM, Valles AS, Ayala V, Kamerbeek C (2010) Boundary lipids in the nicotinic acetylcholine receptor microenvironment. J Mol Neurosci 40:87–90.  https://doi.org/10.1007/s12031-009-9262-z CrossRefPubMedGoogle Scholar
  12. Bermudez V, Antollini SS, Nievas GAF, AveldaÒo MI, Barrantes FJ (2010) Partition profile of the nicotinic acetylcholine receptor in lipid domains upon reconstitution. J Lipid Res 51(9):2629–2641CrossRefGoogle Scholar
  13. Bond PJ, Sansom MSP (2006) Insertion and assembly of membrane proteins via simulation. J Am Chem Soc 128(8):2697–2704.  https://doi.org/10.1021/ja0569104 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Borroni MV, Vallés AS, Barrantes FJ (2016) The lipid habitats of neurotransmitter receptors in brain. Biochimica Biophysica Acta 1858:2662–2670.  https://doi.org/10.1016/j.bbamem.2016.07.005 CrossRefGoogle Scholar
  15. Bouzat CB, Barrantes FJ (1993) Effects of long-chain fatty acids on the channel activity of the nicotinic acetylcholine receptor. Recept Channels 1:251–258PubMedGoogle Scholar
  16. Brannigan G, Hénin J, Law R, Eckenhoff R, Klein ML (2008) Embedded cholesterol in the nicotinic acetylcholine receptor. Proc Natl Acad Sci 105(38):14418–14423CrossRefGoogle Scholar
  17. Breckenridge W, Gombos G, Morgan I (1972) The lipid composition of adult rat brain synaptosomal plasma membranes. Biochimica Biophysica Acta (BBA) 266(3):695–707.  https://doi.org/10.1016/0005-2736(72)90365-3 CrossRefGoogle Scholar
  18. Brusés JL, Chauvet N, Rutishauser U (2001) Membrane lipid rafts are necessary for the maintenance of the (alpha)7 nicotinic acetylcholine receptor in somatic spines of ciliary neurons. J Neurosci 21(2):504–512CrossRefGoogle Scholar
  19. Butler DH, McNamee MG (1993) FTIR analysis of nicotinic acetylcholine receptor secondary structure in reconstituted membranes. Biochimica Biophysica Acta (BBA) 1150(1):17–24.  https://doi.org/10.1016/0005-2736(93)90116-h CrossRefGoogle Scholar
  20. Campagna J, Fallon J (2006) Lipid rafts are involved in c95 (4, 8) agrin fragment-induced acetylcholine receptor clustering. Neuroscience 138(1):123–132CrossRefGoogle Scholar
  21. Carswell CL, Hénault CM, Murlidaran S, Therien J, Juranka PF, Surujballi JA, Brannigan G, Baenziger JE (2015) Role of the fourth transmembrane helix in the allosteric modulation of pentameric Ligand-Gated ion channels. Structure 23(9):1655–64.  https://doi.org/10.1016/j.str.2015.06.020 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Chang HW, Bock E (1977) Molecular forms of acetylcholine receptor: effects of calcium ions and a sulfhydryl reagent on the occurrence of oligomers. Biochemistry 16:4513–4520CrossRefGoogle Scholar
  23. Cheng MH, Xu Y, Tang P (2009) Anionic lipid and cholesterol interactions with \(\alpha 4 \beta 2\) nachr: insights from md simulations. J Phys Chem B 113(19):6964–6970CrossRefGoogle Scholar
  24. Corringer PJ, Poitevin F, Prevost MS, Sauguet L, Delarue M, Changeux JP (2012) Structure and pharmacology of pentameric receptor channels: from bacteria to brain. Structure 20(6):941–956.  https://doi.org/10.1016/j.str.2012.05.003 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Criado M, Eibl H, Barrantes FJ (1982) Effects of lipids on acetylcholine receptor: essential need of cholesterol for maintenance of agonist-induced state transitions in lipid vesicles. Biochemistry 21(15):3622–3629.  https://doi.org/10.1021/bi00258a015 CrossRefPubMedGoogle Scholar
  26. daCosta CJB, Ogrel AA, McCardy EA, Blanton MP, Baenziger JE (2001) Lipid–protein interactions at the nicotinic acetylcholine receptor. J Biol Chem 277(1):201–208.  https://doi.org/10.1074/jbc.m108341200 CrossRefPubMedGoogle Scholar
  27. Feller SE (2008) Acyl chain conformations in phospholipid bilayers: a comparative study of docosahexaenoic acid and saturated fatty acids. Chem Phys Lipids 153(1):76–80.  https://doi.org/10.1016/j.chemphyslip.2008.02.013 CrossRefPubMedGoogle Scholar
  28. Fong T, McNamee M (1986) Correlation between acetylcholine receptor function and structural properties of membranes. Biochemistry 25(4):830–840CrossRefGoogle Scholar
  29. Fong T, McNamee M (1987) Stabilization of acetylcholine receptor secondary structure by cholesterol and negatively charged phospholipids in membranes. Biochemistry.  https://doi.org/10.1021/bi00387a020 CrossRefPubMedGoogle Scholar
  30. Gahbauer S, Böckmann RA (2016) Membrane-mediated oligomerization of g protein coupled receptors and its implications for gpcr function. Front Physiol 7:494.  https://doi.org/10.3389/fphys.2016.00494 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Georgieva R, Chachaty C, Hazarosova R, Tessier C, Nuss P, Momchilova A, Staneva G (2015) Docosahexaenoic acid promotes micron scale liquid-ordered domains: a comparison study of docosahexaenoic versus oleic acid containing phosphatidylcholine in raft-like mixtures. Biochimica Biophysica Acta (BBA) 1848(6):1424–1435.  https://doi.org/10.1016/j.bbamem.2015.02.027 CrossRefGoogle Scholar
  32. Goose JE, Sansom MS (2013) Reduced lateral mobility of lipids and proteins in crowded membranes. PLoS Comput Biol 9(4):1003033.  https://doi.org/10.1371/journal.pcbi.1003033 CrossRefGoogle Scholar
  33. Gotti C, Fornasari D, Clementi F (1997) Human neuronal nicotinic receptors. Prog Neurobiol 53(2):199–237CrossRefGoogle Scholar
  34. Hénin J, Salari R, Murlidaran S, Brannigan G (2014) A predicted binding site for cholesterol on the GABAA receptor. Biophys J 106(9):1938–1949.  https://doi.org/10.1016/j.bpj.2014.03.024 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hibbs RE, Gouaux E (2011) Principles of activation and permeation in an anion-selective cys-loop receptor. Nature 474(7349):54–60CrossRefGoogle Scholar
  36. Humphrey W, Dalke A, Schulten K (1996) VMD—visual molecular dynamics. J Mol Graph 14:33–38CrossRefGoogle Scholar
  37. Ingólfsson HI, Melo MN, Van Eerden FJ, Arnarez C, Lopez CA, Wassenaar TA, Periole X, De Vries AH, Tieleman DP, Marrink SJ (2014) Lipid organization of the plasma membrane. J Am Chem Soc 136(41):14554–14559.  https://doi.org/10.1021/ja507832e CrossRefPubMedGoogle Scholar
  38. Iyer SS, Tripathy M, Srivastava A (2018) Fluid phase coexistence in biological membrane: insights from local nonaffine deformation of lipids. Biophys J 115(1):117–128.  https://doi.org/10.1016/j.bpj.2018.05.021 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Lavandera JV, Saín J, Fariña AC, Bernal CA, González MA (2017) N-3 fatty acids reduced trans fatty acids retention and increased docosahexaenoic acid levels in the brain. Nutr Neurosci 20(7):424–435CrossRefGoogle Scholar
  40. Laverty D, Thomas P, Field M, Andersen OJ, Gold MG, Biggin PC, Gielen M, Smart TG (2017) Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nat Struct Mol Biol.  https://doi.org/10.1038/nsmb.3477 CrossRefPubMedGoogle Scholar
  41. Laverty D, Desai R, Uchański T, Masiulis S, Stec WJ, Malinauskas T, Zivanov J, Pardon E, Steyaert J, Miller KW, Aricescu AR (2019) Cryo-em structure of the human 1 3 2 gaba, javax.xml.bind.jaxbelement@18520d8a, receptor in a lipid bilayer. Nature 565:516–520.  https://doi.org/10.1038/s41586-018-0833-4 CrossRefPubMedGoogle Scholar
  42. Levental K, Lorent J, Lin X, Skinkle A, Surma M (2016) Polyunsaturated lipids regulate membrane domain stability by tuning membrane order. Biophys J.  https://doi.org/10.1016/j.bpj.2016.03.012 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Marchand S, Devillers-Thiéry A, Pons S, Changeux JP, Cartaud J (2002) Rapsyn escorts the nicotinic acetylcholine receptor along the exocytic pathway via association with lipid rafts. J Neurosci 22(20):8891–8901CrossRefGoogle Scholar
  44. Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH (2007) The martini force field: coarse grained model for biomolecular simulations. J Phys Chem B 111(27):7812–7824.  https://doi.org/10.1021/jp071097f CrossRefPubMedPubMedCentralGoogle Scholar
  45. Masiulis S, Desai R, Uchañski T, Serna Martin I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR (2019) Gabaa receptor signalling mechanisms revealed by structural pharmacology. Nature 565:454–459.  https://doi.org/10.1038/s41586-018-0832-5 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Morales-Perez CL, Noviello CM, Hibbs RE (2016a) X-ray structure of the human \(\alpha 4 \beta 2\) nicotinic receptor. Nature 538(7625):411–415.  https://doi.org/10.1038/nature19785 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Morales-Perez CL, Noviello CM, Hibbs RE (2016b) X-ray structure of the human [alpha]4[beta]2 nicotinic receptor. Nature 538(7625):411–415CrossRefGoogle Scholar
  48. Nemecz A, Prevost MS, Menny A, Corringer PJ (2016) Review: emerging molecular mechanisms of signal transduction in pentameric ligand-gated ion channels. Neuron 90:452–470CrossRefGoogle Scholar
  49. Oshikawa J, Toya Y, Fujita T, Egawa M, Kawabe J, Umemura S, Ishikawa Y (2003) Nicotinic acetylcholine receptor alpha 7 regulates cAMP signal within lipid rafts. Am J Physiol Cell Physiol 285(3):C567–74.  https://doi.org/10.1152/ajpcell.00422.2002 CrossRefPubMedGoogle Scholar
  50. Parton D, Tek A, Baaden M, Sansom M (2013) Formation of raft-like assemblies within clusters of influenza hemagglutinin observed by md simulations. PLoS Comput Biol 9(4):e1003034CrossRefGoogle Scholar
  51. Pato C, Stetzkowski-Marden F, Gaus K, Recouvreur M, Cartaud A, Cartaud J (2008) Role of lipid rafts in agrin-elicited acetylcholine receptor clustering. Chemico-Biol Interactions 175(1–3):64–67.  https://doi.org/10.1016/j.cbi.2008.03.020 CrossRefGoogle Scholar
  52. Perillo VL, Peñalva DA, Vitale AJ, Barrantes FJ, Antollini SS (2016) Transbilayer asymmetry and sphingomyelin composition modulate the preferential membrane partitioning of the nicotinic acetylcholine receptor in Lo domains. Arch Biochem Biophys 591:76–86.  https://doi.org/10.1016/j.abb.2015.12.003 CrossRefPubMedGoogle Scholar
  53. Prevost MS, Sauguet L, Nury H, Van Renterghem C, Huon C, Poitevin F, Baaden M, Delarue M, Corringer PJ (2012) A locally closed conformation of a bacterial pentameric proton-gated ion channel. Nat Struct Mol Biol 19(6):642–649CrossRefGoogle Scholar
  54. Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P et al (2013) Gromacs 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics.  https://doi.org/10.1093/bioinformatics/btt055 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Ramarao MK, Cohen JB (1998) Mechanism of nicotinic acetylcholine receptor cluster formation by rapsyn. Proc Natl Acad Sci USA 95(7):4007–4012.  https://doi.org/10.1073/pnas.95.7.4007 CrossRefPubMedGoogle Scholar
  56. Rüchel R, Watters D, Maelicke A (1981) Molecular forms and hydrodynamic properties of acetylcholine receptor from electric tissue. Eur J Biochem 119:215–223CrossRefGoogle Scholar
  57. Sauguet L, Shahsavar A, Poitevin F, Huon C, Menny A, Nemecz A, Haouz A, Changeux JP, Corringer PJ, Delarue M (2014) Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation. Proc Natl Acad Sci 111(3):966–971CrossRefGoogle Scholar
  58. Schindler H, Spillecke F, Neumann E (1984) Different channel properties of torpedo acetylcholine receptor monomers and dimers reconstituted in planar membranes. Proc Natl Acad Sci USA 81:6222–6226CrossRefGoogle Scholar
  59. Scott KA, Bond PJ, Ivetac A, Chetwynd AP, Khalid S, Sansom MSP (2008) Coarse-grained MD simulations of membrane protein-bilayer self-assembly. Structure 16(4):621–630.  https://doi.org/10.1016/j.str.2008.01.014 CrossRefGoogle Scholar
  60. Shaikh SR, Dumaual AC, Castillo A, Locascio D, Siddiqui RA, Stillwell W, Wassall SR (2004) Oleic and docosahexaenoic acid differentially phase separate from lipid raft molecules: a comparative nmr, dsc, afm, and detergent extraction study. Biophys J 87(3):1752–1766.  https://doi.org/10.1529/biophysj.104.044552 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Sharp L, Salari R, Brannigan G (2019) Boundary lipids of the nicotinic acetylcholine receptor: spontaneous partitioning via coarse-grained molecular dynamics simulation. Biochimica Biophysica.  https://doi.org/10.1016/j.bbamem.2019.01.005 CrossRefGoogle Scholar
  62. Sodt AJ, Sandar ML, Gawrisch K, Pastor RW, Lyman E (2014) The molecular structure of the liquid-ordered phase of lipid bilayers. J Am Chem Soc 136(2):725–732.  https://doi.org/10.1021/ja4105667 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Stetzkowski-Marden F, Gaus K, Recouvreur M, Cartaud A, Cartaud J (2006) Agrin elicits membrane lipid condensation at sites of acetylcholine receptor clusters in c2c12 myotubes. J Lipid Res 47(10):2121–2133CrossRefGoogle Scholar
  64. Sunshine C, McNamee MG (1992) Lipid modulation of nicotinic acetylcholine receptor function: the role of neutral and negatively charged lipids. Biochim Biophys Acta 1108(2):240–246.  https://doi.org/10.1016/0005-2736(92)90031-G CrossRefPubMedGoogle Scholar
  65. Turk HF, Chapkin RS (2013) Membrane lipid raft organization is uniquely modified by n-3 polyunsaturated fatty acids. Prostaglandins Leukotrienes Essential Fatty Acids.  https://doi.org/10.1016/j.plefa.2012.03.008 CrossRefGoogle Scholar
  66. Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J Mol Biol 346(4):967–989.  https://doi.org/10.1016/j.jmb.2004.12.031 CrossRefPubMedGoogle Scholar
  67. Unwin N (2017) Segregation of lipids near acetylcholine-receptor channels imaged by cryo-em. IUCrJ 4:393–399.  https://doi.org/10.1107/S2052252517005243 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Wassall SR, Stillwell W (2008) Docosahexaenoic acid domains: the ultimate non-raft membrane domain. Chem Phys Lipids 153:57–63CrossRefGoogle Scholar
  69. Wenz JJ, Barrantes FJ (2005) Nicotinic acetylcholine receptor induces lateral segregation of phosphatidic acid and phosphatidylcholine in reconstituted membranes. Biochemistry 44(1):398–410CrossRefGoogle Scholar
  70. Willmann R, Pun S, Stallmach L, Sadasivam G, Santos AF et al (2006) Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction. EMBO J 25(17):4050–4060CrossRefGoogle Scholar
  71. Yadav RS, Tiwari NK (2014) Lipid integration in neurodegeneration: an overview of Alzheimer’s Disease. Mol Neurobiol 50:168–76CrossRefGoogle Scholar
  72. Yeagle PL (2016) Chapter 7-structures of lipid assemblies. pp 115–154CrossRefGoogle Scholar
  73. Zhu D, Xiong WC, Mei L (2006) Lipid rafts serve as a signaling platform for nicotinic acetylcholine receptor clustering. J Neurosci 26(18):4841–4851.  https://doi.org/10.1523/JNEUROSCI.2807-05.2006 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Zingsheim HP, Neugebauer DC, Frank J, Hänicke W, Barrantes FJ (1982) Dimeric arrangement and structure of the membrane-bound acetylcholine receptor studied by electron microscopy. EMBO J 1:541–547CrossRefGoogle Scholar
  75. Zuber B, Unwin N (2013) Structure and superorganization of acetylcholine receptor-rapsyn complexes. Proc Natl Acad Sci USA 110(26):10622–7.  https://doi.org/10.1073/pnas.1301277110 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Center for Computational and Integrative BiologyRutgers University-CamdenCamdenUSA
  2. 2.Department of PhysicsRutgers University-CamdenCamdenUSA

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